1. Sodium Bicarbonate therapy for Prevention of contrast induced nephropathy of contrast induced nephropathy -A Meta-analysis American Journal of Kidney Diseases, Vol 53, No 4 (April), 2009: pp 617-627 Sankar D. Navaneethan, MD, MPH, Sonal Singh, MD, MPH, Suresh Appasamy, MD, Richard E. Wing, MD, and Ashwini R. Sehgal, MD

2. DEFINITION OF CIN - Elevation of the serum creatinine level by >0.5 mg/dl or > 25% within 3 days of Contrast Material (CM) injection. European Society of Urogenital Radiology guidelines on administeringcontrast media. Abdom Imaging 2003;28: 187–190.

3. introduction

4. WHY IS CIN IMPORTANT TO BE RESEARCHED ON…. 3rd most common cause of hospital-acquired kidney failure(11%). Around 50 million CT procedures are performed annually. Cardiac catheterization and PCI increased 390% between 1979 and 2002 - American Heart Disease and Stroke Statistics-2005 Hospital lengths of stay increase from 5 to 10 days Use of dialysis facilities increases 10% to 15%. Long-term mortality (at 1 year) also increases threefold. The result is that CIN has become an increasing burden on health care resources. Tublin ME, Murphy ME, Tessler FN. Current concepts in contrast media-induced nephropathy. AJR1998; 171:933-939. Iakovou I, Dangas G, Lansky AJ, et al. Incidence, predictors, and economic impact of contrast induced nephropathy.J Am Coll Cardiol. 2002

5. EPIDEMIOLOGY Overall incidence of CIN in the general population is reported to be 0.6–2.3%. Ranges from 10% to 50% in susceptible individuals receiving cardiac angiography, rising in parallel with the baseline serum creatinine level. 1-3 % -- normal renal function 4-11% --mild to moderate renal dysfunction 9-38% -- mild to moderate renal dysfunction + DM / CHF / volume depletion / recent contrast exposure within 72 hrs > 50% i--SCr > 4 mg/dl especially if diabetic ( Parfrey PS, et al. NEJM 1989; 329: 43-149 Rudnick, et al. Kidney Int 1995; 47: 254-261) McCullough P, Sandberg KA. Epidemiology of contrast-induced nephropathy. Rev Cardiovasc Med. 2003;4(suppl 5):S3-S9.

6. PATHOPHYSIOLOGY Renal ischemia Renal ischemia Vasoconstriction - Endothelins Vasoconstriction - Endothelins - Adenosine - Adenosine Role of Osmolality Role of Osmolality Reactive Oxygen Species Reactive Oxygen Species Direct Cellular Toxicity Direct Cellular Toxicity Cleveland Clinic Journal of Medicine January 2006vol. 73 1 75-80

7. RISK FACTORS Fixed (non-modifiable ) 1. Older age 2. DM 3. A/c MI 4. CKD 5. Low LVEF 6. Renal transplant 7. Advanced CHF Modifiable 1. Hypotension 2. Anemia 3. Dehydration 4. Hypoalbuminemia 5. Drugs- ACE inhibitors, diuretics, NSAIDS, Nephrotoxic antibiotics 6. IABP 7. Volume of CM used 15-55% each 100 ml increment in contrast volume resulted in a 30% increase in the odds of CIN

8. PREVENTION STRATEGIES - THE BACKGROUND OF THE STUDY Normal saline solution hydration is the most widely accepted preventive intervention. N- acetylcysteine may be effective...but studies have given conflicting results. Sodium bicarbonate hydration is of value, but larger multicenter studies are needed to see efficacy The low osmolar contrast agents are less nephrotoxic... but can still cause nephropathy. Hemofiltration, though found effective in high risk, still need larger RCTs to be performed before it be recommended. Theophylline cannot yet be recommended as standard prophylaxis against contrast- induced nephropathy

9. How is Hydration helpful? Decreases activity of RAA system Decrease levels of vasoconstrictors Increase Na diuresis Decrease T-G feedback Prevent Tubular obstruction Protects from ROS Dilute the contrast material

10. Action of Sodium Bicarbonate? -It decreases the reactive oxygen species formation as this is a pH dependent process – HABER-WEISS reaction ( less in alkalinized urine).

11. AIMS & OBJECTIVES To Study the OUTCOME OF HYDRATION WITH IV SODIUM BICARBONATE vs HYDRATION WITH NORMAL SALINE in patients undergoing contrast procedures. Primary- Contrast Induced Nephropathy Secondary- Need for RRT, In-Hospital Mortality, Length of Hospital stay, CCF, Change in Bicarbonate levels. DEF- Rise in S.Cr by 25% or 0.5mg% above baseline within 96 hours.

12. methods

13. STUDY DESIGN& OUTCOME  A Meta-analysis using the MEDLINE database(1966 to Jan 2008), EMBASE(Jan 2008) & abstracts from conference proceedings.  OUTCOMES: Contrast Induced Nephropathy Need for Renal Replacement Therapy In-Hospital Mortality Congestive Heart Failure Change in Bicarbonate levels

14. SEARCH STRATEGY Citations selected using Heading terms- CIN, Sodium bicarbonate, Hydration and RCTs References of each studies No language restrictions 2 reviewers screened all abstracts independently and in duplicate Eligibility of the full-text articles assessed.

15. ELIGIBILITY CRITERIA RCTs for prevention of CIN (any duration) INTERVENTION- Hydration with sodium bicarbonate vs normal saline, with or without N-AC. PARTICIPANTS- Any contrast procedure irrespective of renal status. (Elective/Emergency) Studies should report the Incidence

17. STATISTICAL ANALYSIS Dichotomous data - OR and its 95%CI Cont. Variables - Weighted mean diff and its 95%CI Risks were pooled by DerSimonian-Laird random effects model Heterogeneity testing- by Cochrane Q statistic and I square test Quality assessment was done by the Modified Jadad score.

18. STATISTICAL ANALYSIS(Contd) Sensitivity Analysis -Effect of statistical models -Influence of each studies Subgroup Analysis -Severity of renal disease -Setting -Publication status All analysis in RevMan4.2.10 software

20. TREATMENT REGIMEN 154 mEq/L of sodium bicarbonate at 3mL/kg/h for 1 hour before contrast, then 1 mL/kg/h for 6 hours after contrast( same for normal saline).

21. RESULTS

22. CONTRAST INDUCED NEPHROPATHY Significantly decreased risk (12 trials, 1,652 patients; n=75 of 829 versus 128 of 823; OR=0.46; 95% CI= 0.26 to 0.82; P 0.008).

24. Subgroup analysis: 1. NaHCO3 alone vs Normal saline alone: (7 trials, 839 patients; OR= 0.39; 95% CI- 0.20 to 0.77; P= 0.006) 2. NaHCO3+N-AC vs Normal saline+ N-AC: (8 trials, 813 patients; OR=0.68; 95% CI- 0.34 to 1.37; P =0.3)

25. NEED FOR RRT (9 trials, 1,215 patients; n =5 of 612 versus 10 of 603; OR= 0.50, 95% CI= 0.16 to 1.53; P=0.2) No significant difference

27. IN HOSPITAL MORTALITY (11 trials, 1,640 patients; 4 of 826 versus 9 of 814; OR= 0.51; 95%, CI= 0.15 to 1.69; P=0.3) No signifucance

28. CONGESTIVE HEART FAILURE 7 studies No difference -(OR=0.85; 95% CI= 0.32 to 2.24; P= 0.7) CHANGE IN BICARBONATE LEVELS 2 studies Increased -(weighted mean difference, =2.77 mEq/L; 95% CI= 1.94 to 3.61; P =0.001)

29. SENSITIVITY ANALYSIS Effect of statistical model: Fixed effects model- (OR= 0.54; 95% CI=0.39 to 0.73; P = 0.001). Effect of studies: Similar results Elective vs Emergency: Elective -- (OR= 0.47; 95%CI=0.24 to 0.90; P = 0.02) Emergency--(OR=0.13; 95% CI= 0.04 to 0.48; P = 0.002)

30. Limited to GFR< 60: (OR=0.42; 95% CI= 0.22 to 0.79 ; P = 0.007) Published vs Unpublished: Published-- (OR=0.26; 95% CI=0.10 to 0.64; P =0.004) Unpublished-- (OR=0.85; 95% CI=0.46 to1.57; P=0.6)

32. DISCUSSION & CRITICAL APPRAISAL

33. SUMMARY Lower incidence of CIN with hydration using Sodium bicarbonate. (Reduced the odds of CIN by 54% of what it would have been compared to Sodium Chloride) No significant change in need for RRT and Mortality Safe in terms of worsening CCF/pulmonary edema

34. MERITS Addresses an important issue with great implications in future……. Outcomes are convincing regarding successfulness of the intervention. Similar results in both fixed and random effects models. Subgroup analyses supporting the overall statistical significance.

35. DEMERITS Paucity of quality data Heterogeneity Publication bias Lack of a fixed definition Short duration trials ( Patient centered outcomes not focused) Lack of patient-level data The optimum regimen? Generalization to all contrast procedures?

36. CONCLUSION Sodium bicarbonate hydration is an acceptable alternative and probably superior to normal saline for prevention of CIN Adequately powered trials measuring patient centered outcomes, With different underlying risks, and undergoing variety of contrast procedures are needed……..

37. CURRENT RECOMMENDATIONS NSAIDs should be discontinued before contrast exposure. Hydration -Normal saline. -Sodium Bicarbonate Hydration. Smallest volume of contrast Avoid Hypotension N-Acetyl Cysteine 600mg bd before and after RFT to be done 48 to 72 hrs post procedure.

38. THANK YOU

39. Merten et al An RCT at a single center, compared hydration with sodium bicarbonate vs sodium chlorideto prevent contrast-induced nephropathy in azotemic patients receiving low-osmolar contrast agents. Both infusions contained 154 mEq of either sodium chloride or sodiumbicarbonate in 1 L of 5% dextrose and water.A.The infusion rate for either fluid was 3mL/kg/hour for 1 hour before contrastadministration, followed by 1 mL/kg/hour during contrast administration and then for6 hours afterward. Contrast-induced nephropathy occurredin 1.7% of patients who received sodium bicarbonate compared with 13.6% of patientswho received sodium chloride (P =.02).

40. OZCAN et al -efficacy of sodium bicarbonate by comparing 2 other regimens, including combination of N- acetylcysteine (NAC) plus sodium chloride and sodium chloride alone, to prevent CIN in patients undergoing cardiovascular procedures. METHODS: 264 patients scheduled for cardiovascular procedure, with a baseline S.Cr >1.6 RESULTS: There were no significant differences among groups regarding baseline demographic properties and nephropathy risk factors. The change in creatinine clearance was significantly better in the sodium bicarbonate group than other 2 groups (P =.007). The incidence of CIN was significantly lower in the sodium bicarbonate group (4.5%) compared with sodium chloride alone (13.6%, P =.036) and tended to be lower than in the combination group (12.5%, P =.059). CONCLUSIONS: Hydration with sodium bicarbonate provides better protection against CIN than the sodium chloride infusion does alone. Combination therapy of NAC plus sodium chloride did not offer additional benefit over hydration with sodium chloride alone.

41. RENO study METHODS:a prospective, controlled, randomized, single-center trial in 111 consecutive patients with acute coronary syndrome undergoing emergency PCI. As part of the hydration therapy, 56 patients (group A) received an infusion of sodium bicarbonate plus N-acetylcysteine (N- AC) started just before contrast injection and continued for 12 h after PCI. The remaining 55 patients (group B) received the standard hydration protocol consisting of intravenous isotonic saline for 12 h after PCI. In both groups, 2 doses of oral N-AC were administered the next day. RESULTS: The 2 groups were similar with respect to age, gender, diabetes mellitus, and baseline serum creatinine. A serum creatinine concentration >0.5 mg/dl from baseline after emergency PCI was observed in 1 patient in group A (1.8%) and in 12 patients in group B (21.8%; p < 0.001). Acute anuric renal failure was observed in 1 patient (1.8%) in group A and in 7 patients (12.7%) in group B (p = 0.032).

42. REMEDIAL trial METHODS : 326 consecutive patients with chronic kidney disease, referred for coronary and/or peripheral procedures, were randomly assigned to prophylactic administration of 0.9% saline infusion plus NAC (n=111), sodium bicarbonate infusion plus NAC (n=108), and 0.9% saline plus ascorbic acid plus NAC (n=107). All enrolled patients had S.Cr > or = 2.0 mg/dL and/or eGFR < 40 mL x min(-1) x 1.73 m(-2). The amount of contrast media administered (179+/-102, 169+/-92, and 169+/-94 mL, respectively; P=0.69) and risk scores (9.1+/-3.4, 9.5+/-3.6, and 9.3+/-3.6; P=0.21) were similar in the 3 groups. RESULTS:CIN occurred in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P=0.019 by Fisher exact test versus saline plus NAC group), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P=1.00 versus saline plus NAC group).

43. BRAR et al Randomized, controlled, single-blind study enrolling 353 patients with stable renal disease who were undergoing coronary angiography at a single US center. Included patients were 18 years or older and had an eGFR of 60 mL/min per 1.73 m(2) or less and 1 or more of diabetes mellitus, history of congestive heart failure, hypertension, or age older than 75 years. INTERVENTIONS: Patients were randomized to receive either sodium chloride (n = 178) or sodium bicarbonate (n = 175) administered at the same rate (3 mL/kg for 1 hour before coronary angiography, decreased to 1.5 mL/kg per hour during the procedure and for 4 hours after the completion of the procedure). RESULTS: Median patient age was 71 (interquartile range, 65-76) years, and 45% had diabetes mellitus. The groups were well matched for baseline characteristics. The primary end point was met in 13.3% of the sodium bicarbonate group and 14.6% of the sodium chloride group (relative risk, 0.94; 95% confidence interval, 0.55-1.60; P =.82). In patients randomized to receive sodium bicarbonate vs sodium chloride, the rates of death, dialysis, myocardial infarction, and cerebrovascular events did not differ significantly at 30 days (1.7% vs 1.7%, 0.6% vs 1.1%, 0.6% vs 0%, and 0% vs 2.2%, respectively) or at 30 days to 6 months (0.6% vs 2.3%, 0.6% vs 1.1%, 0.6% vs 2.3%, and 0.6% vs 1.7%, respectively) (P >.10 for all).

44. CIN RISK ASSESSMENT TOOL

45. Subgroup analysis after omitting a study

47. QUALITY ASSESSMENT - MODIFIED JADAD SCORE